19-1482081-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_017573.5(PCSK4):​c.1946G>T​(p.Cys649Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,552,464 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0054 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0099 ( 86 hom. )

Consequence

PCSK4
NM_017573.5 missense

Scores

2
6
10

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.832
Variant links:
Genes affected
PCSK4 (HGNC:8746): (proprotein convertase subtilisin/kexin type 4) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. The protease is expressed only in the testis, placenta, and ovary. It plays a critical role in fertilization, fetoplacental growth, and embryonic development and processes multiple prohormones including pro-pituitary adenylate cyclase-activating protein and pro-insulin-like growth factor II. [provided by RefSeq, Jan 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010106891).
BP6
Variant 19-1482081-C-A is Benign according to our data. Variant chr19-1482081-C-A is described in ClinVar as [Benign]. Clinvar id is 2648935.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAdExome4 at 86 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCSK4NM_017573.5 linkc.1946G>T p.Cys649Phe missense_variant Exon 15 of 15 ENST00000300954.10 NP_060043.2 Q6UW60-1A0A140VJQ9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCSK4ENST00000300954.10 linkc.1946G>T p.Cys649Phe missense_variant Exon 15 of 15 1 NM_017573.5 ENSP00000300954.5 Q6UW60-1

Frequencies

GnomAD3 genomes
AF:
0.00543
AC:
826
AN:
152184
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00171
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00991
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00474
AC:
704
AN:
148602
Hom.:
4
AF XY:
0.00463
AC XY:
376
AN XY:
81296
show subpopulations
Gnomad AFR exome
AF:
0.00131
Gnomad AMR exome
AF:
0.00254
Gnomad ASJ exome
AF:
0.000121
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000172
Gnomad FIN exome
AF:
0.00259
Gnomad NFE exome
AF:
0.00985
Gnomad OTH exome
AF:
0.00577
GnomAD4 exome
AF:
0.00990
AC:
13866
AN:
1400162
Hom.:
86
Cov.:
33
AF XY:
0.00966
AC XY:
6688
AN XY:
692098
show subpopulations
Gnomad4 AFR exome
AF:
0.00116
Gnomad4 AMR exome
AF:
0.00268
Gnomad4 ASJ exome
AF:
0.000674
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000250
Gnomad4 FIN exome
AF:
0.00270
Gnomad4 NFE exome
AF:
0.0120
Gnomad4 OTH exome
AF:
0.00989
GnomAD4 genome
AF:
0.00542
AC:
826
AN:
152302
Hom.:
1
Cov.:
33
AF XY:
0.00475
AC XY:
354
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.00171
Gnomad4 AMR
AF:
0.00261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00282
Gnomad4 NFE
AF:
0.00991
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00706
Hom.:
2
Bravo
AF:
0.00547
ESP6500AA
AF:
0.00101
AC:
4
ESP6500EA
AF:
0.00852
AC:
67
ExAC
AF:
0.00230
AC:
257
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
May 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PCSK4: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.74
D
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.53
T
MetaRNN
Benign
0.010
T
MetaSVM
Benign
-0.42
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-7.0
D
REVEL
Benign
0.26
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.94
P
Vest4
0.55
MVP
0.60
MPC
0.79
ClinPred
0.098
T
GERP RS
2.8
Varity_R
0.72
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs78359732; hg19: chr19-1482080; API